Myeloid-cell-specific role of Gasdermin D in promoting lung cancer progression in mice

Traughber, C. Alicia; Deshpande, Gauravi; Neupane, Kalash; Bhandari, Nilam; Khan, Mariam R.; McMullen, Megan R.; Swaidani, Shadi; Opoku, Emmanuel; Muppala, Santoshi; Smith, Jonathan; Nagy, Laura E.; Gulshan, Kailash

doi:10.1016/j.isci.2023.106076

Cited by 8 publications

(3 citation statements)

References 47 publications

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“…The other players in the inflammasome pathway such as Gasdermin-D are is also involved in the macrophage inflammasome-dependent proliferation of cancer where lung metastasis in Gasdermin D -/- mice was reduced ( 30 ). Similar to our study, macrophage gasdermin-D plays a role in the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Macrophage IL-1β contributes to tumorigenesis through paracrine AIM2 inflammasome activation in the tumor microenvironment

et al. 2023

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Intracellular recognition of self and non-self -nucleic acids can result in the initiation of effective pro-inflammatory and anti-tumorigenic responses. We hypothesized that macrophages can be activated by tumor-derived nucleic acids to induce inflammasome activation in the tumor microenvironment. We show that tumor conditioned media (CM) can induce IL-1β production, indicative of inflammasome activation in primed macrophages. This could be partially dependent on caspase 1/11, AIM2 and NLRP3. IL-1β enhances tumor cell proliferation, migration and invasion while coculture of tumor cells with macrophages enhances the proliferation of tumor cells, which is AIM2 and caspase 1/11 dependent. Furthermore, we have identified that DNA-RNA hybrids could be the nucleic acid form which activates AIM2 inflammasome at a higher sensitivity as compared to dsDNA. Taken together, the tumor-secretome stimulates an innate immune pathway in macrophages which promotes paracrine cancer growth and may be a key tumorigenic pathway in cancer. Broader understanding on the mechanisms of nucleic acid recognition and interaction with innate immune signaling pathway will help us to better appreciate its potential application in diagnostic and therapeutic benefit in cancer.

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Section: Discussionmentioning

confidence: 99%

Macrophage IL-1β contributes to tumorigenesis through paracrine AIM2 inflammasome activation in the tumor microenvironment

et al. 2023

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“…Further, GSDMD was required for the infiltration of CD8 + T cells into the tumor microenvironment (TME) of NSCLC to ensure an immune response, whereas GSDMD deficiency increased the cytolytic capacity of CD8 + T cells ( 53 ). GSDMD knockout markedly decreased lung cancer metastasis in a metastatic lung carcinoma cell model ( 54 ). Chen et al ( 19 ) reported that in NSCLC cell lines, GSDMD knockdown promoted caspase-3-induced apoptosis independent of other apoptotic stimuli, and GSDMD suppression inhibited tumor growth in a mouse model.…”

Section: Gsdmdmentioning

confidence: 99%

Role of gasdermin family proteins in cancers (Review)

Yang

Tang

2023

Int J Oncol

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The gasdermin (GSDM) family comprises six proteins, including GSDMA-GSDME and Pejvakin. Most of these proteins have a crucial role in inducing pyroptosis; in particular, GSDMD and GSDME are the most extensively studied proteins as the executioners of the pyroptosis process. Pyroptosis is a highly pro-inflammatory form of programmed cell death and is closely associated with the incidence, development and prognosis of multiple cancer types. The present review focused on the current knowledge of the molecular mechanism of GSDM-mediated pyroptosis, its intricate role in cancer and the potential therapeutic value of its anti-tumor effects.

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“…Studies have shown that GSDMD deletion or inhibition notably decreases pyroptosis and remarkably protect mice from sepsis, which is a fatal condition requiring urgent medical solutions ( 12 – 14 ). In addition, GSDMD acts as an effector of inflammasome signaling and is implicated in several human diseases, including nonalcoholic steatohepatitis ( 15 ), cardiovascular disease ( 16 ), inflammatory bowel disease ( 17 ), type II diabetes ( 17 , 18 ), rheumatoid arthritis ( 19 ), cancer ( 20 , 21 ), and Alzheimer’s disease ( 22 ). Consequently, on account of the crucial function of GSDMD in pyroptosis, it has emerged as an ideal and attracting target for therapeutic intervention of inflammasome-driven diseases.…”

Section: Introductionmentioning

confidence: 99%

NU6300 covalently reacts with cysteine-191 of gasdermin D to block its cleavage and palmitoylation

Jiang,

Zhang,

Cai

et al. 2024

Sci. Adv.

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Gasdermin D (GSDMD) serves as a vital mediator of inflammasome-driven pyroptosis. In our study, we have identified NU6300 as a specific GSDMD inhibitor that covalently interacts with cysteine-191 of GSDMD, effectively blocking its cleavage while not affecting earlier steps such as ASC oligomerization and caspase-1 processing in AIM2- and NLRC4-mediated inflammation. On the contrary, NU6300 robustly inhibits these earlier steps in NLRP3 inflammasome, confirming a unique feedback inhibition effect in the NLRP3-GSDMD pathway upon GSDMD targeting. Our study reveals a previously undefined mechanism of GSDMD inhibitors: NU6300 impairs the palmitoylation of both full-length and N-terminal GSDMD, impeding the membrane localization and oligomerization of N-terminal GSDMD. In vivo studies further demonstrate the efficacy of NU6300 in ameliorating dextran sodium sulfate–induced colitis and improving survival in lipopolysaccharide-induced sepsis. Overall, these findings highlight the potential of NU6300 as a promising lead compound for the treatment of inflammatory diseases.

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Myeloid-cell-specific role of Gasdermin D in promoting lung cancer progression in mice

Cited by 8 publications

References 47 publications

Macrophage IL-1β contributes to tumorigenesis through paracrine AIM2 inflammasome activation in the tumor microenvironment

Macrophage IL-1β contributes to tumorigenesis through paracrine AIM2 inflammasome activation in the tumor microenvironment

Role of gasdermin family proteins in cancers (Review)

NU6300 covalently reacts with cysteine-191 of gasdermin D to block its cleavage and palmitoylation

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